CD8+ T cells can destroy established solid tumors, but relapse is common. Two major rate limiting steps are: lack of proper priming or block in the effector phase. This program focusses on solid tumors that represent the majority of human cancers. Local barriers imposed by the solid tumor microenvironment not only impede radiation and chemotherapy but also CD8+ T cell-mediated tumor destruction. This makes cancer recurrence after these therapies a common problem. Clinical cancers usually harbor at least 10A9 cancer cells containing a variable number of cancer stem cells. These cancer cells are genetically diverse, and the expectation that any single therapy or mechanism will eradicate the entire population of cancer cells seems unrealistic. Therefore, this proposal is not only to induce, restore and improve destructive power of CD8+ T cells, but to find strategies for enlisting additional mechanisms and treatments in a predictably synergistic way. Project 1 will study the factors that will mediate and define innate factors that can lead to successful T cell priming in response to a growing tumor with particular emphasis on type I interferons and downstream factors like IL-1 leading to cross-priming of CD8+ T cells. Project 2 will target mice with established solid tumors, distant metastases and determine whether intratumoral LIGHT treatment in conjunction with anti-Her2/neu antibody can increase tumor cell apoptosis and thereby increase CD8+ T cell priming and alter the tumor microenvironment to allow T cell maturation to a full effector stage. Project 3 will study the requirements and possible limitations of using engineered T cell receptors for the destruction of solid tumors. Project 4 will exploit the finding that targeting the stroma of solid tumors CD8+ T cells can prevent escape of cancer variants from therapy. The Protein Expression and Peptide Core will provide the proteins and peptides needed for the above projects, while the Administrative/Statistics/Optical Imaging Core will overlook the projects, give statistical advice and allow optical imaging analysis in real time of the events occurring in the tumor microenvironment following manipulations proposed in the four projects. CD8+ T cells can destroy well-established solid tumors but relapse is very common. The goal is to (i) manipulate and target the tumor microenvironment to overcome recurrence from therapy and (ii) explore novel immunological concepts and engineered reagents that can synergize with other novel as well as conventional therapies.